The number of cells in multicellular organisms is kept in balance by proportionate cell growth and death. Although, cell growth has been most extensively studied, it has become increasingly clear that cell death is also carefully regulated. Thus, in the healthy organism most cells die as a result of the controlled activation of processes that break down cellular components. Well studied examples of such processes include internucleosomal fragmentation of DNA by endonucleases, and activation of selected protease. In addition to ensuring a balance in cell numbers, apoptosis is a major mechanism for eliminating potential harmful cells such as autoreactive lymphocytes and cells with DNA damage. This is clearly demonstrated in lpr/lpr mice where lack of the APO-1 receptor results in deficient apoptotic signaling and a failure to eliminate autoreactive lymphocytes. As a consequence the mice stiffer from antoimmune disease. Defective cell death is also an important factor in carcinogenesis. Results showing that successful anti-cancer therapy, including irradiation and many antineoplastic drags, induce apoptosis in cancer cells suggest that information about the mechanisms of cell death may be of value for designing therapy aiming to remove disease-causing cells.
Although certain features of apoptotic cells seem to reflect a final common pathway for physiologic cell death, the suicidal process is still poorly characterized. The intracellular signaling pathways that lead to activation of the lytic enzymes are also largely unknown. Tyrosine kinases and phosphatases are, however, likely to play important roles as dysregulated tyrosine kinases induce immortality and resistance to chemotherapy in certain cell types. This has been timber supported by studies showing effects of tyrosine kinase and phosphatase inhibitors on apoptosis, some of which indicate that these enzymes may be targets for phamcological manipulation of apoptosis. Most of the studies on regulation of tyrosine phosphorylation in apoptosis have, however, focused on immediate changes in tyrosine phosphorylation induced by apoptotic stimuli. Very little is known about changes in cellular phosphorylation status that occur later in the process when cells commit to apoptosis. Although important for understanding the effects inhibitors and stimulators of tyrosine phosphorylation, such downstream phenomena, that occur over long time periods, are difficult to study as apoptosis in a cell population is rarely synchronized. Any sample may therefore contain cells at different stages in the process thereby complicating the analysis of data obtained by analysis of whole cell suspensions.